Approximately 2.7 million Americans aged 65 and older spent at least one day in the intensive care unit (ICU) costing MEDICARE a total of $27.5 billion. Up to 80% of these older ICU patients had delirium during their hospital stay that affects negatively and independently their hospital related health outcomes. Older adults with delirium receive potentially harmful medications such as anticholinergics and benzodiazepines and are more prone to falls, injuries, pressure ulcers and restraints than their counterparts with no delirium. These complications contribute to prolonged ICU and hospital length of stay, higher mortality rates, poorer functional status, limited rehabilitation, increased institutionalization, and higher health care costs. Currently, there is no FDA-approved pharmacological compound to reduce mortality and morbidity related to delirium. Disturbances in several neurotransmitters, such as acetylcholine, dopamine, glutamate, serotonin, norepinephrine, and gamma-aminobutyric acid (GABA), have been suggested to be involved in the pathophysiology of delirium. These neurotransmitters are put forward as potential targets for the development of pharmacological therapeutics for delirium. However, the strongest data supports a critical therapeutic role for acetylcholine enhancement, GABA reduction, and dopamine reduction. Pharmaco-epidemiological studies and scattered randomized clinical trials have demonstrated that the pharmacological management of delirium among older adults is complicated and may need to include a combination of a reduction in the use of benzodiazepines and anticholinergics, along with the use of low dose neuroleptics such as haloperidol. However, there have been no randomized controlled trials evaluating the efficacy of such a pharmacological management on reducing delirium severity, duration, and its related complications. This proposal is seeking funding to conduct a randomized controlled trial that would evaluate the efficacy of a pharmacological protocol for delirium that includes 1) a reduction of exposure to anticholinergic medications; 2) a reduction of exposure to benzodiazepines; and 3) daily use of a low dose of haloperidol. The primary outcomes of the study are delirium severity, as measured by the Delirium Rating Scale (DRS-R-98); and delirium duration as measured by the Confusion Assessment Method in the ICU (CAM-ICU). PUBLIC HEALTH RELEVANCE: Hospitalized older adults suffering from Delirium are a vulnerable and rapidly growing segment of our patient population, especially those admitted to the Intensive Care Units. During their hospital and ICU stay, these patients are prone to develop various hospital acquired complications such as falls, injuries, pressure ulcers, and restraints. Subsequently, these complications contribute to mortality, poorer functional status, limited rehabilitation, prolonged length of stay, increased institutionalization, and higher health care costs. Evidence suggests that a specific disturbance in the neurotransmitter function is involved in the pathophysiology of delirium and that modifying the levels of these neurotransmitters may decrease the severity and duration of delirium and thus improving mortality and morbidity of patients with delirium. The primary goal of this proposal is to conduct a randomized controlled clinical trial that will evaluate the efficacy of a multi-component pharmacological intervention in reducing delirium severity and duration and subsequently decrease ICU and hospital length of stay. A major advantage of the proposed individualized intervention is reducing exposure to potentially harmful medications and using low dose of haloperidol during the critical early days of ICU care.